Naphthyl acetaldehyde derivatives,methods of use thereof

ABSTRACT

2-(2&#39;&#39;-NAPHTHYL) ACETALDEHYDE DERIVATIVES OPTIONALLY SUBSTITUTED AT THE 2 POSITION AND/OR POSITIONS C-1&#39;&#39;,4&#39;&#39;,5&#39;&#39;,7&#39;&#39; OR 8&#39;&#39;; AND/OR POSITION C-6&#39;&#39; OR POSITIONS C-5&#39;&#39; AND 7&#39;&#39; EXHIBIT ANTI-INFLAMMATORY, ANALGESIC, ANTIPYRETIC AND ANTIPRURITIC ACTIVITY.

United States Patent 3,663,713 NAPHTHYL ACETALDEHYDE DERIVATIVES,METHODS OF USE THEREOF John Fried and Ian T. Harrison, Palo Alto,Calif., assignors to Syntex Corporation, Apartado, Panama No Drawing.Continuation-impart of application Ser. No. 741,900, July 2, 1968. Thisapplication Apr. 9, 1969, Ser. No. 814,855

Int. Cl. A61k 27/00 US. Cl. 424-333 9 Claims ABSTRACT OF THE DISCLOSURE2 (2' anaphthyl) acetaldehyde derivatives optionally substituted at the2 position and/or positions C1',4,5,7' or 8; and/or position C-6' orpositions C- and 7 exhibit anti-inflammatory, analgesic, antipyretic andantipruritic activity.

R R R R I II n 7 5 13 7 e a a a wherein, R is -CHR R CH(OH) (NH or-CH(OH) (SO Y) wherein R and R are alkoxy, cycloalkoxy,cycloalkylmethoxy, 2-cycloalkylethoxy, 3-cycloalkylpropoxy, monocyclicarylmethoxy, 2-phenylethoxy, 3-phenylpropoxy, alkanoyloxy,cycloalkanoyloxy, cycloalkyl acetoxy, cycloalkylpropionyloxy, monocyclicarylacetoxy; or R and R taken together are =0, =NR 3-hydroxypropylene-1,2-dioxy, -OCHR CHR O-- or wherein R is alkyl, cycloalkyl,cycloalkylmethyl, 2-cycloalkylethyl, monocyclic arylmethyl, phenethyl,hydroxy, alkoxy, cycloalkoxy, cycloalkyl methoxy, 2-cycloalkylethoxy,benzyloxy, 2-phenylethoxy, amino or carbamoylamino; each of R and Rindependently of each other is hydrogen, alkyl, cycloalkyl,cycloalkylmethyl, 2-cycloalkylethyl, monocyclic arylmethyl, ormonocyclic aryl; R is hydrogen, methyl; ethyl or propyl; Y is sodium orpotassium, one of R and R is hydrogen, the other is hydrogen, methyl,ethyl or difiuoromethyl; or R and R taken together are methylene,halomethylene or ethylene;

3,663,713 Patented May 16, 1972 R (at position C-1,4 or 8) is hydrogen,alkyl, trifluoromethyl, fluoro, chloro, hydroxy, a conventionalhydrolyzable ester, oxyether or thioether;

R (at position C-5,6 or 7) is alkyl, cycloalkyl, hydroxymethyl,alkoxymethyl, trifluoromethyl, vinyl, ethynyl, fluoro, chloro, hydroxy,a conventional hydrolyzable ester, oxyether, thioether, formyl, acetylor monocyclic aryl;

Each of R R (at position C-1,4,7 or 8), R and R is alkyl, fluoro,chloro, hydroxy, a conventional hydrolyzable ester, oxyether orthioether, provided that when one of R and R or one of R and R ishydroxy, oxyether or thioether, the other is the identical group oralkyl, fluoro, chloro, or a conventional hydrolyzable ester; and R (atposition 0-5) is alkyl, fluoro, chloro, bromo, hydroxy, a conventionalhydrolyzable ester, oxyether or thioether; provided when one of R and R(at position C-S) is hydroxy, oxyether or thioether, the other is theidentical group or alkyl, fluoro, chloro, bromo (R only i.e., only R isbromo, R is not bromo) or a conventional hydrolyzable ester.

In the preferred embodiment of the present invention, R and R aremethoxy, ethoxy, propoxy, cyclopentyloxy, cyclohexyloxy, benzyloxy,phenethyloxy, tolyloxy, acetoxy, propionyloxy, valeryloxy, caproyloxy,cyclopentylcarbonyloxy, cyclohexylcarbonyloxy, phenylacetoxy; 01' R andR taken together are :0, methylimino, ethylimino, isopropylimino,cyclopentylimino, cyclohexylimino, benzylimino, p-methylbenzylimino,phenethylimino, phenylimino, tolylimino, hydroxyimino, methoxyimino,ethoxyimino, i-propoxyimino, cyclopentyloxyimino, cyclohexyloxyimino,benzyloxyimino, p-methylbenzyloxyimino, phenethyloxyimino, aminoimino,carbamoylamino, ethylenedioxy, 1,2 propylenedioxy, 1,3 propanedioxy, 3hydroxypropylene 1,2 dioxy, 2,3 butanedioxy, 1,2 diphenylethylenedioxy,1,2 dicyclopentylethylenedioxy, 1,2 dibenzylethylenedioxy, 2,2 dimethyl1,3- propanedioxy or 2-phenyl-1,3-propanedioxy; Y is sodium; one of Rand R is hydrogen, the other is hydrogen, methyl or difiuoromethyl; or Rand R taken together are methylene or difluoromethylene; R (at positionC-1,4 or 8) is hydrogen, methyl, ethyl, isopropyl, trifiuoromethyl,fluoro, chloro, methoxy, methoxymethyloxy, difluoromethoxy, methylthio,methoxymethylthio or difluoromethylthio; R (at position C-5,6 or 7) ismethyl, ethyl, isopropyl, cyclopropyl, trifluoromethyl, vinyl, ethynyl,fluoro, chloro, methoxy, methoxymethyloxy, difluorornethoxy, methylthio,methoxymethylthio or difiuoromethylthio', each of R R (at positionC-1,4,7 or 8), R and R is methyl, ethyl, isopropyl, fluoro, chloro,methoxy, methoxymethyloxy, difiuoromethoxy, methylthio,methoxymethylthio, or difluoromethylthio, provided that when one of R orR, or one of R and R is methoxy, methoxymethyloxy, difluoromethoxy,methylthio, methoxymethylthio or difluoromethylthio, the other is theidentical group or methyl, ethyl, isopropyl, fluoro or chloro; and R (atposition 0-5) is methyl, ethyl, isopropyl, fluoro, chloro, methoxy,methoxymethyloxy, difluoromethoxy, methylthio, methoxymethylthio ordifiuoromethylthio; provided when one of R and R (at position 0-5) ismethoxy, methoxymethyloxy, difiuoromethoxy, methylthio,methoxymethylthio, or difluoromethylthio, the other is the identicalgroup or methyl, ethyl, isopropyl, fluoro, chloro or bromo (R only). R(at position C-S) is methyl, ethyl, isopropyl, fluoro, chloro, bromo,trifluoromethyl, methoxy, methoxyrnethyloxy, difluoromethoxy,methylthio, methoxymethylthio or difluoromethylthio, the other is theidentical group or methyl, ethyl, isopropyl, fluoro, chloro or chloro (Ronly).

By the term alkyl is meant branched or straight chain hydrocarbon atoms,such as methyl, ethyl, propyl, iso- 3 propyl, butyl, tertiarybutyl,pentyl, hexyl, and the like. By the term cycloalkyl is meant cyclichydrocarbon groups of three to seven carbon atoms, such as cyclopropyl,cyclopentyl, cyclohexyl, and the like.

The term monocyclic aryl defines a phenyl group optionally substitutedwith one to two methyl, ethyl, isopropyl, methoxy, hydroxy, fluoro, orchloro groups. Typical monocyclic aryls include phenyl, 2-tolyl,3-tolyl, 4-tolyl, 2,4-dimethylphenyl, 2,6-dimethylphenyl, 3-ethylphenyl,4- ethylphenyl, 4-isopropylphenyl, Z-methoxy, 4-methoxyphenyl,2,4-dimethoxyphenyl, 3-hydroxyphenyl, 2,6-dihydroxyphenyl,2-chlorophenyl, 2,6dichlorophenyl, 3-fiuorophenyl, 4-fluorophenyl,2,4-difluorophenyl, 2,3-difluorophenyl, 2,3,4-trifluorophenyl,parachlorophenyl, 2,4-dihydroxyphenyl, 2,4-dimethoxyphenyl and the like.

The term alkanoyloxy defines a straight or branched saturatedhydrocarbon carbonyloxy group of from 1 to 12 carbon atoms. Typicalalkanoyloxy groups include acetoxy, propionyloxy, butyryloxy,4-methylvalryloxy, caproyloxy, Z-methylbutyryloxy, capryloxyloxy,pelarglyloxy, capryloxy, 9-methylcapryloxy, lauroyloxy, and the like.

The term alkoxy defined a straight or branched chain hydrocarbon ethergroup of six or less carbon atoms, including methoxy, ethoxy, 2-propoxy,propoxy, butoxy, 3- pentoxy, and the like. By the term alkoxymethyloxyis meant methylether groups substituted with one alkoxy group; typicalalkoxymethyloxy groups include methoxymethyloxy, ethoxymethyloxy,isopropoxymethyloxy, and the like.

By the term alkylthio is meant straight or branched chain hydrocarbonthioether groups of six or less carbon atoms, including methylthio,ethylthio, propylthio, 2-propylthio, Z-butylthio, pentylthio,3-hexylthio, and the like. By the term alkoxymethylthio is meantmethylthio ether groups substituted with one alkoxy group, such asmethoxymethylthio, ethoxymethylthio, 2-propoxymethylthio, and the like.

The term cycloalkyloxy defines a cyclic hydrocarbon ether group of fromthree to seven carbon atoms. Typical cycloalkyloxy includecyclopentyloxy and cyclohexyloxy.

By the term monocyclic aralkyloxy is meant an alkoxy substituentsubstituted with one monocyclic aryl group. Typical monocyclicaralkyloxy include: 2,6-dimethylbenzyloxy and p-chlorophenylthyloxy.

The term alkanoyloxy defines an alkylcarbonyloxy group. Typicalalkanoyloxy groups include acetoxy, butyryloxy, and capryloxy. The termcycloalkanoyloxy defines a monocyclic cycloalkylcarbonyloxy group. Theterm monocyclic aralkanoyloxy defines an aralkyl carbonyloxy group suchas phenylacetyloxy.

By the term halomethylene is meant monoor dihalomethylene groups whereinhalo is fluoro or chloro. The preferred halomethylenes includefluoromethylene, difluoromethylene, fluorochloromethylene andchloromethylene.

The term conventional hydrolyzable ester, as used herein, denotes thosehydrolyzable ester groups conventionally employed in the art, preferablythose derived from hydrocarbon carboxylic acids or their salts. The termhydrocarbon carboxylic acid defines both substituted and unsubstitutedhydrocarbon carboxylic acids. These acids can be completely saturated orpossess varying degrees of unsaturation (including aromatic), can be ofstraight chain, branched chain, or cyclic structure and preferablycontain from one to twelve carbon atoms. Typical conventionalhydrolyzable esters thus included within the scope of the term and theinstant invention are acetate, propionate, Z-methyl propionate,butyrate, valerate, caproate, enanthate, caprylate, benzoate,phenylacetate, diethylacetate, trimethylacetate, t-butylacetate,cyclohexylacetate, cyclopentylpropionate, adamantoate, bicyclo-[2.2.2]octy1 carboxylate, hemisuccinate, hemiadipate,hemi-[3,/3-dimethylflutarate, and the like.

The term oxyether, as used herein, denotes those ether groupsconventionally employed in the art, preferably those derived fromstraight chain, branched chain, aromatic hydrocarbons and oxoheterocyclic hydrocarbons. The term hydrocarbon defines both saturatedand unsaturated hydrocarbons. These designated hydrocarbons areoptionally substituted With groups such as hydroxy, alkoxy, halo,alkylthio, and the like. Preferably the hydrocarbons contain from one totwelve carbon atoms. Typical oxyethers thus include alkoxy,difluoromethoxy, alkoxymethyloxy, tetrahydrofuran-2.-yloxy,tetrahydropyran-2'-yloxy and 4-a1koxytetrahydropyran-4-yloxy.

The term thioether, as used herein, denotes those thio ether groupsconventionally employed in the art, preferably those derived fromstraight chain, branched chain, cyclic and aromatic hydrocarbons. Theterm hydrocarbon defines both saturated and unsaturated hydrocarbons.These hydrocarbons are optionally substituted with groups such ashydroxy, alkoxy, alkylthio, halo and the like. Preferably thehydrocarbons contain from one to twelve carbon atoms. Typical thioethersthus include alkylthio, difluoromethylthio, alkoxymethylthio, and thelike.

When one of R and R is hydrogen and the other is methyl, ethyl ordifluoromethyl, the compounds of Formulas I, II, III and IV exist aspairs of enantiomorphs. Each enantiomorph or optical isomer of thecompounds of Formulas I, II, III and IV is included within the presentinvention. In some instances, one enantiomorph exhibits greateranti-inflammatory, analgesic, anti-pyretic and/or anti-pruritic activitythan the corresponding other enantiomorph. Nevertheless, the presentcompounds of Formulas I, II, III and IV that exist as pairs ofenantiomorphs can be administered as mixtures of enantiomorphs or asindividual enantiomorphs.

The individual enantiomorphs or optical isomers of the compounds ofFormulas I, II, II and IV are prepared from the corresponding individualresolved enantiomorphs or optical isomers of the starting material. Anenantiomorph of Formulas I, II, III and IV and the correspondingresolved starting material will not necessarily have the same opticalrotation although they will have the same absolute configuration.

The 2-(2'-naphthyl) acetaldehydes and derivatives thereof Formulas I,II, III and IV exhibit anti-inflammatory, analgesic, anti-pyretic andanti-pruritic activity. Accordingly, these compounds are employed in thepresent method of effecting treatment of inflammation, pain, pyrexia andpruitus in mammals, such as mice, rats, dogs monkeys or humans.

These compounds are useful in the treatment of inflammation of the skin,respiratory tract, muscularskeletal system, joints, internal organs, andtissues. Accordingly, these compounds are useful in the treatment ofconditions characterized by inflammation, such as contact dermatitis,allergic conditions, burns, rheumatism, contusion, arthritus, bonefracture, post-traumatic conditions and gout. In those cases in whichthe above conditrons include pain, pyrexia and pruritus, coupled withthe inflammation, the instant compounds are useful for relief of theseconditions as well as the inflammation. The instant compounds are usefulin the treatment of pain associated with post-operative conditions,post-traumatic conditions, post-partum conditions, dysmenorrhea, burns,gout, contusions, neuralgia, neuritis, headache and rheumatic fever. Asstated above, these compounds also exhibit anti-pyretic activity;accordingly, these compounds are useful in the treatment of pyrexiawhere reduction of a fever is indicated, for example, in the treatmentof high fevers associated with diseases such as rheumatic fever,bronchitis, pneumonia, typhoid fever, and Hodgkins disease. The presentcompounds are also useful in the treatment of pruritus where thecondition exists contemporaneously with inflammation, pain and/or fever.More over, the compounds are useful for treating pruritus per se.

Although the above compounds of Formulas I-IV exhibit anti-inflammatory,analgesic, anti-pyretic and antipruritic activity, certain groups of theabove compounds exhibit remarkably enhanced specific activity whileretaining the other types of activity. For example, the compounds ofFormula II Where R is at position C-6 exhibit enhanced anti-inflammatoryactivity together with analgesic, anti-pyretic and anti-pruriticactivity. Accordingly, the compounds of Formula II would be very usefulin treating a condition characterized by a high degree of inflammationtogether with moderate degree of pain. The and 7 substituted compoundsof Formula II and the compounds of Formula IV exhibit superior analgesicactivity together with anti-inflammatory, anti-pyretic and anti-pruriticactivity. Accordingly, the 5 and 7 substituted compounds of Formula Iand the compounds of Formula IV are very useful to treat conditionscharacterized by a high degree of pain together with a moderate degreeof inflammation, fever and pruritus.

The preferred manner of oral administration provides the use of aconvenient daily dosage regimen which can be adjusted according to thedegree of aflliction. Generally, a daily dose of from 0.01 mg. to 100mg. of the active compound per kilogram of body weight of the mammal isemployed. Most conditions respond to treatment comprising a dosage levelin the order of 1 mg. to 5 mg. per kilogram of body weight per day. Forsuch oral administration, a pharmaceutically acceptable nontoxiccomposition formed by the incorporation of any of the normally employedexcipients. Suitable pharmaceutical excipients include starch, glucose,lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel,magnesium carbonate, magnesium stearate, sodium stearate, glycerylmonostearate, talc, sodium chloride, dried skim milk, glycerol,propylene glycol, water, ethanol, and the like. These compositions takethe form of solutions, suspensions, tablets, pills, capsules, powders,sustained release formulations, and the like. In addition, thesecompounds can be administered in conjunction with other medicinal agentsdepending upon the specific conditions being treated.

-A measure of anti-inflammatory activity according to the carrageenininduced edema assay of Winter et al., Iroceedings of the Society forExperimental Biology and Medicine 111, 544 (1962) shows the following:that 2-(-6'-methoXy-2-naphthyl) propionaldehyde to have over three timesthe activity of phenylbutazone; that the semicarbazone of 2-(6'-methoxy-2'-naphthyl) propionaldehyde has over three times the activityof phenylbutazone; that 1-hydroxyimino-2-(6-methoxy-2'-naphthyl) propanehas over two times the activity of phenylbutazone; that1,l-dimethyl-Z-(6-methoxy-2'-naphthyl) propane is as active asphenylbutazone; and that the sodium bisulfite addition product of 2-(6'-methoxy-2'-naphthyl) propionaldehyde has about three times theactivity of phenylbutazone.

Similar standard assays to measure anti-pyretic activities show2-(6'-methoxy-2'-naphthyl) propionaldehyde and the sodium bisulfiteaddition product thereof to have over fourteen and seventeen times,respectively, the antipyretic activity of aspirin.

Included within the compounds of Formulas I, II, III and IV are thenovel 2-(2-naphthyl) acetaldehyde derivatives of the following formulas:

'1 6 14 e R R n s m R R R16 wherein,

R, R and R are as defined above.

R (at position C-1, 4 or 8) is trifiuoromethyl, fluoro, chloro, hydroxy,a conventional hydrolyzable ester of thioether;

R (at position C-5 or 7) is alkyl, cycloalkyl, hydroxymethyl,alkoxymethyl, trifiuoromethyl, vinyl, ethynyl, fluoro, chloro, hydroxy,a conventional hydrolyzable ester, oxyether, thioether, formyl, acetylor aryl;

R is alkyl, cycloalkyl, hydroxymethyl, alkoxymethyl, trifiuoromethyl,vinyl, ethynyl, fluoro, chloro, hydroxy, a conventional hydrolyzableester, alkoxymethyloxy, difluoromethoxy, tetrahydropyran-2-yloxy,tetrahydrofuran-2'- yloxy, 4-alkoxy-tetrahydropyran-4'-yloxy; thioether,formyl, acetyl or aryl; and

Each of R and R (at positions C-1, 4, 7 or 8), R and R is alkyl, fluoro,chloro, hydroxy, a conventional hydrolyzable ester, oxyether orthioether; provided that when one of R or R or one of R or R is hydroxy,oxyether or thioether the other is the identical group or alkyl, fluoro,or chloro or a conventional hydrolyzable ester; and

R (at position C-S) is alkyl, fluoro, chloro, bromo, hydroxy, aconventional hydrolyzable ester, oxyether or thioether; provided whenone of R and R (at position C-S) is hydroxy, oxyether or thioether theother is the identical group or alkyl, fluoro, chloro, bromo (R only),or a conventional hydrolyzable ester.

In the preferred embodiment of the novel compounds of Formulas V, VI,VII, VIII and IX, R and R are methoxy, ethoxy, cyclopentyloxy,cyclohexyloxy, benzyloxy, phenethyloxy, tolyloxy, acetoxy, propionyloxy,valeryloxy, caproyloxy, cyclopentylcarbonyloxy, cyclohexylcarbonyloxy,phenylacetyloxy or tolylacetoyloxy; or R and R taken together are =0,methylimino, ethylimino, isopropylimino, cyclopentylimino,cyclohexylimino, benzylimino, p-methoxybenzylimino, phenethylimino,phenylimino, tolylimino, hydroxyimino, methoxyimino, ethoxyimino,isopropoxyimino, cyclopentyloxyimino, cyclohexyloxyimino,benzyloxyimino, p-methylbenzyloxyimino, phenethyloxyimino, aminoimino,carbamoylamino, ethylenedioxy, 1,2-propylenedioxy, 1,3-propanedioxy,S-hydroxypropylene 1,2 dioxy, 2,3'-butanedioxy,1,2-diphenylethylenedioxy, 1,2-dicyclopentylethylenedioxy,1,2-dibenzylethylenedioxy, 2,2-dimethyl-1,3-propanedioxy or2-phenyl-1,3-propanedioxy; Y is sodium; one of R and R is hydrogen, theother is hydrogen, methyl or difiuoromethyl; or R and R taken togetherare methylene or difiuoromethylene; R (at position C-1, 4 or 8) istrifiuoromethyl, fluoro, chloro, methylthio, methoxymethylthio ordifluoromethylthio; R (at position C-S or 7) is methyl, ethyl,isopropyl, cyclopropyl, trifiuoromethyl, vinyl, ethynyl, fluoro, chloro,methoxy, methoxymethyloxy, difluoromethoxy, methylthio,methoxymethylthio or difluoromethylthio; R is methyl, ethyl, isopropyl,cyclopropyl, trifiuoromethyl, vinyl, ethynyl, fluoro, chloro,methoxymethyloxy, difluoromethoxy, methylthio, methoxymethylthio, ordifluoromethylthio; each of R", R (at position C-1, 4, 7 or 8), R and Ris methyl, ethyl, isopropyl, fluoro, chloro,

methoxy, methoxymethyloxy, difluoromethoxy, methylthio,methoxymethylthio or difluoromethylthio; provided that when one of R orR or one or R or R is methoxy, methoxymethyloxy, difluoromethoxy,methylthio, methoxymethylthio, or difluoromethylthio, the other is theidentical group or methyl, ethyl, isopropyl, fluoro or chloro; and R (atposition C-S) is methyl, ethyl, isopropyl, fluoro, chloro, bromo,methoxy, methoxymethyloxy, difiuoromethoxy, methylthio,methoxymethylthio or difiuoromethylthio; provided when one of R and R(at position C-5 is methoxy, methoxymethyloxy, difluoromethoxy,methylthio, methoxymethylthio or difluoromethylthio, the other is theidentical group or methyl, ethyl, isopropyl, fiuoro, chloro or bromo (Ronly i.e., R is bromo, R is not bromo).

An especially preferred group of novel 2-(2'-naphthyl) acetaldehydederivatives are those of Formulas VI, VII, VIII and IX wherein R, R R RR R R R R R and R are defined in the above immediate paragraph.

The present compounds of Formulas I, II, III and IV (wherein R is CHO)are prepared from the corresponding 2-naphthyl acetic acid derivativesor esters thereof via a novel process which can be illustrated by thefollowing reaction scheme A:

wherein,

R and R are as defined above and R is hydrogen or alkyl. In the abovescheme, the naphthyl moiety of the 2-(2'-naphthyl) acetic acidderivatives of Formula X and of the 2-(2'-naphthyl) acetaldehydederivatives of Formula XI are substituted with (1) a R group at positionC-1, 4 or 8; (2) a R group at position C-5, 6 or 7; (3) a R at positionC-6 and a R at position C-1, 4, 5, 7 or 8; or (4) a R and R group atpositions C-5 and C-7 respectively.

The novel process of Scheme A is conducted by treating the startingcompound of Formula X, a 2-(2'-naphthyl) acetic acid derivative or esterthereof, with lithium aluminum hydride in an inert organic ethersolvent, such as di ethyl ether, tetrahydrofuran, and the like. If afree 2-(2'- naphthyl) acetic acid derivative is used as a startingmaterial, at least 0.75 molar equivalent of lithium aluminum hydride areused, and preferably about 1.0 to 2.5 molar equivalents are used. If anester of a 2-(2-naphthyl) acetic acid derivative is used as a startingmaterial, at least 0.5 molar equivalent of lithium aluminum hydride areused, and preferably about 0.6 to 2.0 molar equivalents are used. Thereduction is carried out at a temperature between C. and the boilingpoint of the solvent employed, preferably between 15 C. to 35 C. Thesecond step of the above process consists of adding ethyl acetate to thereaction mixture diluting the resulting mixture with water (at least 8ml. of water per gram of alkali metal hydride), filtering andevaporating it. The resulting residue is treated with chromium trioxidein acetic acid or pyridine or ace tone containing 8 N sulfuric acid. Theprocess is carried out at a temperature between 0 C. and 50 C.,preferably the reaction temperature is between C. and 30 C. At leastmolar equivalent of chromium trioxide are used per molar equivalent ofthe acid starting material and preferably about 1.5 to about 2.5 molarequivalents of chromium trioxide are used.

Alternatively, the first step can be carried out by treating thecompound of Formula X with diborane in tetrahydrofuran at about roomtemperature. One to two molar equivalents of diborane per molarequivalent of the starting compound are usually sufficient.

Alternatively, the second step can be carried out by treating theresidue obtained from the first step of the reaction withdicyclohexylcarbodiimide (DCC) and anhydrous phosphoric acid in dimethylsulfoxide at about room temperature. Generally, three molar equivalentsof DCC and /2 molar equivalent of anhydrous phosphoric acid are used permolar equivalent of the starting compound of Formula X used in the firststep.

At the completion of the above process, the compound of Formula XI, theproduct, is isolated by conventional means. For example, the reactionmixture is extracted with ethyl acetate; the extract is filtered, washedto neutrality, dried and evaporated. The product can be further purifiedby conventional techniques such as crystallization or chromatography.

Certain groups present in the starting compound of Formula X are reducedby lithium aluminum hydride or diborane. For example, an acetyl group isreduced to an a-hydroxy ethyl group and a formyl group is reduced to ahydroxy methyl group. These reduced groups are regenerated after thecompletion of the first step of the above process via an oxidationprocess using manganese dioxide (active) in an inert organic solvent,such as acetone, petroleum ether, and the like, at about roomtemperature.

In the second step of the above process, certain groups will beoxidized. For example, hydroxymethyl and hydroxy groups will beoxidized. These groups can be advantageously protected by esterifyingthese groups prior to the oxidation step of Scheme A. The groups can beregenerated after the above process by hydrolysis of the esterifiedgroups such as with an aqueous base, such as aqueous sodium carbonate.

The acetals of the compounds of Formula XI are prepared by treating thealdehyde products with alcohols, such as methanol,

propanol,

butanol,

isopentanol,

neopentanol,

hexanol,

isohexanol,

cyclopropanol,

cyclobutanol,

cyclopentanol, cyclobutylmethanol, cyclohexylmethanol,2-cyclopropylethanol, 2-cyclohexylethanol, 3-cyclopropylpropanol,3-cyclopentylpropanol, phenylmethanol, p-tolylmethanol,3-chlorophenylmethanol, 3,S-dihydroxyphenylmethanol,2,4-diethylphenylmethanol, 4-methoxyphenylmethanol, 2-phenylethanol,3-phenylpropanol, 1,2-butandiol,

1,3-butandiol,

1,4'-butandiol,

2,3-butandiol, 1,2,4-butantriol, 2-n-butyl-2-ethyl-1,3-propanediol,2,2-diethyl-1,3-propancdiol, 2,2-dimethyl-1,3-propanediol,2,2-diphenyl-1,3-propanediol, 2-ethyl-l,3-hexanediol,2-ethyl-2-methyl-1,3-propanediol, Z-methyl-Z-propyl-1,3-propanediol,1,2-pentanediol,

2,3 -pentanediol, 2,2-dimethyl-1,3-pentanediol,3-methyl-2,'4-pentanediol, 2,3-hexanediol, 3,4-hexanediol,2-ethyl-1,3-hexanediol,

9 3 -methyl-2,4-heptane diol, 2,3-octanediol, 4, S-octanediol,ethyleneglycol, 1,2-propanediol, 1,2-octanediol, 2, 3 -nonanediol, 4,5-nonanediol, 1,2-dodecanediol, 2,3-dodecanediol, 6,7-dodecanediol,1,2-decane diol, cyclopentylethyleneglycol,1,2-dicyclohexylethyleneglycol, 3-cyclopropyl-1,2-propanediol,1-cyc1obutyl-2, 3-hexanediol, 4-cyclopentyl-1,2-butanediol,1,6-dicyc1opentyl-4,5 -hexanediol, 1, 3 -dicyclopropyl-1,2-propanediol,1-cyclopentyl-S-cyclohexyl-2,3-pentanediol, 3 -phenyl1,2-propanediol, 1-(4'-tolyl -2,3-tridecanediol, 1-cyclohexyl-3- (2'-methoxy-henyl) -1,2-propanediol, 1-cyclopenty1-4- 3 -chlorophenyl) -2,3-butanediol,l-cyclopropyl-S- (4'-hydroxyphenyl) -2,3-pentanediol, 1,4-di (2',6'-dimethylphenyl -2,3-butanediol, phenylethylene glycol, 1-(4'-ethylphenyl -2,3 -heptanediol, 1-cyclohexyl-Z-phenylethyleneglycol,1-cyclopentyl-3 -phenyl-2, 3-propanediol, 1-cyclobutyl-4-(4-isopropylphenyl) -3,4-butanediol, 1 ,3-diphenyl-1,2-prpanediol,1,2-diphenylethyleneglycol, 1,3-propanediol, 2-methyl- 1,3-propanediol,2-cyclohexyl-1,3-propanediol, 2-cyclopentylmethyl-1,3-propanediol,2-(2'-cyclopropylethyl)-1,3-propanediol, 2-benzyl-1,3-propanediol2-phenyl-l,3propanediol, 2,2-dimethyl-1 ,3-propanediol,2,2-diethyl-1,3-propanediol, 2,2-dipropyl-1,3 -propanediol,2,2-dipentyl-1,3-propanediol, Z-methyl-Z-ethyl-1,3-propanediol,Z-methyl-Z-propyl-1,3-propanediol, 2-ethyl-2-propyl-1,3-propanediol,2-ethy1-2-butyl-1, 3-propanediol, 2,2-dicyclopentyl-1,3-propanediol,2,2-di(cyclohexylmethyl)-1,3-pr0panediol,Z-cyclohexylethyl-2-hexyl-1,3-propanediol, 2,2-dibenzyl-1,3-propanediol,2,2-diphenyl-1,3-propanediol, 2-ethyl-2- 3 '-tolyl)-1,3propanediol,' 2-(4'-methylbenzyl) -2- (4'-tolyl)-1,3-propanediol, 2,4-pentanediol, 3,5-heptanediol, 4, 6-nonanediol, 2-ethyl-2-butyl-1,3-propanediol,2,2-diethyl-1,3 -butanediol, 2-hexyl-2-cyclohexy1- 1 ,3 -butanediol,3-methyl-2-cyclohexyl-2,4pentanediol, 2,2-di(cyclopropylmethyl)-1,3-pentanediol, 3 ,3-dimethyl-2,4-pentanediol, 3,3-diphenyl-2,4-pentanediol, 3 3-dihexyl-2,4-pentanediol,3-methyl-3-phenyl-2,4-peutanediol, 3-cyclopropyl-2,4-hexanediol, 2- 3'-ethylphenyl) -1, 3-hex ane diol, 3,3-dibenzyl-2,4-hexanediol, 3-(4'-methoxyphenyl) -2,4-heptanediol, 4,4-diethyl-3 ,5 -heptanediol,4,4-dicyclohexyl-3 ,5 -heptanediol, 3,3-di (cyclohexylethyl)-2,4-heptanediol, 4-benzyl-4-phenyl-3,5-heptanediol,

1 0 4-cyclobutylethyl-3,S-octanediol, 4,4-dimethyl-3,S-octanediol,4-cyclohexylmethyl-4-benzyl-3,S-octanediol,5-cyclopentylmethyl-4,6-nonanediol, 5,5-dipropyl-4,6-nonanediol,5,5-dipentyl-4,6-nonanediol, ethanol, 2-propanol, propanol, 2-pentanol,ethylene glycol, 1,2-propylene glycol, propane-1,3-di0l, glycerine andthe like, in the presence of an acid catalyst, such as p-toluenesulfonicacid, perchloric acid and the like.

The oxime derivatives of the compounds of Formula XI are prepared byrefluxing the aldehyde product with hydroxylamine hydrochloride ormonosubstituted hydroxylamine hydrochloride in the presence of pyridinein absolute ethanol to yield the corresponding oxime or 1-monosubstituted oxyimino derivatives. The product is isolated byevaporating the reaction mixture. The product is further purified bycrystalization or chromatography. Typical monosubstituted hydroxylaminehydrochlorides used in the process include the hydrochloride salts ofmethoxyamine, butoxyamine, 2 butoxyamine, pentoxyamine, 3 pentoxyamine,hexoxyamine, cyclopropoxyamine, cyclobutoxyarnine, cyclohexoxy,cyclopentylrnethoxyamine, cyclohexylmethoxyarnine,2-cyclopentylethoxyamine, 2 cyclohexylethoxyethoxyamine,cyclopropylethoxyamine, cyclobutylmethoxyamine, benzyloxyamine,2-phenylethoxyamine, and the like. The hydrazone derivatives of thecompounds of Formula X'I are prepared by treating the aldehyde productwith hydrazine in the presence of sulfuric acid or hydrochloric acid inmethanol or ethanol. The semicarbazone derivatives of the compounds ofFormula XI are prepared by heating the aldehyde prod- 'ucts with anunsubstituted or substituted semicarbazide hydrochloride salt and sodiumacetate in ethanol and Water. The semicarbazone, hydrazone and oximederivatives of the compounds of Formula XI can be further purified byrecrystallization from ethanol-water. When the 2- (2-naphthyl)acetaldehyde derivative is substituted with an acetyl group, only 1.1molar equivalents of semicarbazine hydrochloride, hydrazone orhydroxylamine hydrochloride is employed and the product is purified bychromatographing on alumina or silica.

The hydroxy amino derivatives of the compounds of Formula XI areprepared by treating the aldehyde products with anhydrous ammonia gas inan anhydrous solvent such as diethylether. The resulting hydroxy aminoderivatives are isolated by filtration.

The bisulfite addition derivatives of the compounds of Formula XI areprepared by treating the aldehyde products with a saturated aqueoussolution of sodium bisulfite. The bisulfite addition derivatives can bepurified by crystallization.

The unsubstituted and substituted imino derivatives of the compounds ofFormula XI are prepared by treating the aldehyde product with anhydrousammonia or a monosubstitute amine in a halogenated hydrocarbon solventat a temperature of from about 70 C. to about 50 0, preferably at 0 C.to give the corresponding l-(unsubstituted or substituted)amino-2(2-naphthyl) ethanol derivative. The latter is heated betweenabout 30 C. and C., preferably about 50 C., under reduced pressure toyield the corresponding l-(unsubstituted or substituted) iminoderivatives. Typical monosubstituted amines that are used include:methylamine, propylamine, hexylamine, isopentylamine, cyclopropylamine,cyclobutylmethylamine, cyclopentylmethylamine, 2-cyclopropylethylamine,2 cyclohexylethylamine, benzylamine, 4'- methylbenzylamine,2',6-difluor0benzylamine, phenethyl amino and the like.

When a resolved optical isomer of a 2-(2'-naphthyl) acetic acid startingcompound of Formula IX is employed in the above process, thecorresponding resolved optical isomer of the compound of Formula X isobtained.

The 2-(2'-naphthyl) acetic acid starting materials of Formula X areknown and can be prepared by any one of several methods fully describedin our co-pending US. application No. 608,997, filed Jan. 13, 1967; No.694,771, filed Dec. 7, 1967 and No. 741,858, filed July 2, 1968.

One method is to treat a l-tetralone, optionally substituted at positionC5, 6, 7 or 8, or disubstituted at position C-6 and C5, 7 or 8,sequentially with (1) an alkyl carbonate and an alkali metal hydride,(2) an alkali metal hydride and an ot-haloacetic acid and (3) an aqueousmineral acid to obtain the corresponding 2- (carboxymethyl)-1-tetralone.The latter is reduced with sodium borohydride to form the corresponding1,2,3,4- tetrahydro-l-hydroxy-2-naphthyl acetic acid; this resultingproduct is hydrogenolyzed with hydrogen in the presence of ahydrogenation catalyst, such as a palladium catalyst; the resultingproduct is esterified and then dehydrogenated with palladium on charcoalcatalyst at about 180 C. to furnish the corresponding Z-naphthyl aceticacid ester derivative.

The starting compounds of Formula X that are substituted at position -1are prepared from the corresponding 2-(carbomethoxymethyl)-l-tetralonesby treating the latter (1) with a phosphorous pentahalide to introduce ahalo group at the C1 position or (2) with alkyl magnesium bromide andthen with aqueous mineral acid to alkylate at the C1 position or (3)with trialkyl orthoformate in the presence of an acid catalyst to add analkoxy group at position C1; and then dehydrogenating the resultinghalogenated or alkylated or alkoxylated product by refluxing with2,3-dichloro-5,6-dicyano-1,4- benzoquinone. By employing6-substituted-2-(carbomethoxymethyl)-l-tetralones in the aboveprocesses, the corresponding 1-substituted-6-substituted compounds ofFormula ]X are prepared.

The starting compounds of Formula IX substituted at position C-4 ordisubstituted at positions C-4 and 6 are prepared from unsubstituted and6-substituted 3-(carbomethoxymethyl) tetralones, respectively, via theprocesses used to prepare 1-substituted-2-naphthyl acetic acids from2-(carboxymethyl) tetralones, Z-(carboxymethyl) tetralones are preparedvia the process described in J. Chem. Soc. (London) 1922, 1717.

The Z-naphthyl acetic acid starting materials that are substituted at Cor C7 with a cycloalkyl, hydroxymethyl, alkoxymethyl, vinyl, ethynyl,formyl, acetal, or

7, 1967, employed in the preparation of l-tetralones, similarlysubstituted at C6. For example, a S-methyl-l-tetralone is ketalized withethylene glycol and p-toluenesulfonic acid and then treated with N-bromosuccinimide to yield the corresponding S-bromomethyl derivative which isdeketalized by acid hydrolysis. The S-bromomethyl compounds are treatedwith potassium acetate in dimethylformamide, and then hydrolyzed withaqueous base to yield the corresponding S-hydroxymethyl-l-tetralones.The S-hydroxymethyl group is etherified by conventional means; such astreating the S-hydroxymethyll-tetralone with sodium hydride and methyliodide to obtain the corresponding 5-methoxymethyl-l-tetralone. TheS-hydroxymethyl-l-tetralone is 'ketalized and oxidized with manganesedioxide to yield the corresponding S-formyl-l-tetralone ketal compound.When the latter is treated with methylmagnesium bromide thecorresponding 5-(1- methyl-l-hydroxymethyl)-1-tetralone ketal isobtained, which when dehydrated with heat in the presence of acid yieldsthe corresponding 5-vinyl-1-tetralone. The S-ethynyl-l-tetralone isprepared by treating the corresponding 5-vinyl compound with a molarequivalent of bromine and then debrominating the resulting dibromoproduct with potassium hydroxide. The S-acetal-l-tetralone is preparedby oxidizing the 5-(1'-methyl-1-hydroxyn1ethy)-ltetralone with chromiumtrioxide in 8 N sulfuric acid. The S-cycloalkyl-l-tetralone is preparedby treating the corresponding S-chloro-l-tetralone with ethylene glycoland p-toluenesulfonic acid and then with magnesium in tetrahydrofuran toyield the corresponding Grignard reagent; this in turn is treated withthe corresponding oxoalkyl, such as cyclohexanone, to obtain thecorresponding 5-(l-hydroxycycloalkyl)-l-tetralone ketal. The latter isacid hydrolyzed and then hydrogenolyzed with a molar equivalent ofhydrogen in the presence of Raney nickel to yield the corresponding5-cycloalkyl compound. The 5-aryl-1-tetralones can be prepared bytreating l-tetralon- 5-yl magnesium chloride ketal, prepared asdescribed above, with an unsubstituted or substituted cyclohexenone intetrahydrofuran to yield the corresponding S-(unsubstituted orsubstituted)cyclohexadienyl-l-tetralone ketal, which upon a milddehydrogenation in the presence of 5% palladium on charcoal at about C.and acid hydrolysis yields the corresponding S-(unsubstituted orsubstituted)-phenyl1-tetralone. Similarly, the7-substituted-l-tetralones can be prepared from 7-methyl-1-tetralone and7-chloroor 7-bromo-1-tetralone by means of the above describedprocesses.

The distubstituted 2-(2-naphthyl) acetic acid derivatives of Formula Xare prepared by the methods disclosed in our copending US. application608,997, filed Jan. 13, 1967, 694,771 filed Dec. 7, 1967 and 741,858filed July 2, 1968. For example, 2-(5',6'-disubstituted-2-naphthyl)acetic acid derivatives are prepared by treating methyl phenylacetatewith at least 2 molar equivalents of a 2- substituted succinicanhydride, such as Z-methoxy succinic anhydride, and at least 2 molarequivalents of aluminum chloride in nitrobenzene or carbon disulfide toyield the corresponding methyl p- 3 '-carboxy-3-substituted-1-oxopropyl) phenyl acetate derivative, which when treatedstituted-1'-oxopropyl) phenyl acetate derivatives. The derivatives areseparated by conventional means, such as by chromatography ordistillation. The 1'-oxo group of the 2-substituted derivative isselectively reduced with sodium borohydride to a 1'-hydroxy group. The1-hydroxy derivative is esterified by treatment with acetic anhydride inpyridine. The resulting 1-acetoxy derivative is treated with thionylchloride, phosphorus trichloride or phosphorus pentachloride to yieldthe corresponding methyl p-(3'-chlorocarbonyl-2'-substituted 1acetoxypropyl phenyl acetate derivative, Which when treated with atleast 3 molar equivalents of aluminum chloride in benzene yields thecorresponding 7-carbomethoxymethyl-4-acetoxy-3-substituted-l-tetralone,which is selectively reduced with sodium borohydride to give thecorresponding methyl 2-(5'-acetoxy-6-substituted-8'-hydroxy-5,6,7',8'-tetrahydro-2-naphthyl) acetate. The litter is esterified withacetic anhydride and pyridine and selectively hydrogenolyzed with amolar equivalent of hydrogen in the presence of a palladium catalyst toyield methyl 2-(5-acetoxy-6-substituted 5,6',7',8 tetrahydro 2'-naphthyl) acetate derivative, which is hydrolyzed with aqueous base,such as with 5% aqueous sodium bicarbonate solution, and esterified withdiazomethane to yield the corresponding methyl2-(5'-hydroxy-6-substituted- 5',6',7,8'-tetrahydro-2-naphthyl) acetatederivative. The latter is treated with at least 2 molar equivalents ofN,N- diethyl-N-(1,l,2-trifiuoro-2-chloroethyl) amine in methylenechloride and then it is refluxed with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone in xylene to yield the corresponding methyl 2-(5 '-fluoro-6'-substituted-2-naphthyl) acetate. The 5'-hydroxyderivative is heated with a thioalkane in the presence of acid at aboutC. in a sealed container to yield the corresponding methyl2-(5-alkylthio-6'-substituted-2'-naphthyl) acetate. The 5'-hydroxyderivative is oxidized with chromium trioxide in acetic acid to yieldthe corresponding methyl 2-(5-oxo-6'-substituted-2'-naphthyl) acetatederivative. The oxo derivative is treated with phosphorus pentachlorideand then refluxed in 2,3-dichloro-5,6-dicyano-1,4-benzoquinone in xyleneto yield the corresponding 2-(5-chloro-6'-substituted-2-naphthyl) aceticacid. The 5-chloro derivative is refluxed with cuprous bromide indimethyl sulfoxide to yield the corresponding methyl2-(5-bromo-6'-substituted- 2-naphthyl) acetate derivative; by employingcuprous iodide in place of cuprous bromide, the corresponding 5'- iododerivative is obtained. The 5'-oxo derivative is treated with at least amolar equivalent of an alkyl magnesium bromide, then acid hydrolyzed andfinally heated with 5% palladium on charcoal to about 180 C. to yieldthe corresponding 2-(5'-alkyl-6-substituted-2'-naphthyl) acetic acid.The 5-oxo derivative is treated with trialkyl orthoformate in thepresence of an acid catalyst, such as ptoluenesulfonic acid in an arylhydrocarbon solvent, and then it is refluxed with BBQ in xylene to yieldthe corresponding methyl 2-(5'-alkoxy-6-substituted-2'-naphthyl) acetatederivative. The 3'-substituted-1'-oxo derivative, prepared as describedabove, is selectively reduced with sodium borohydride, treated withthionyl chloride or the like, treated with aluminum chloride in benzene,esterified with acetyl chloride, selectively reduced with sodiumborohydride, dehydrogenolyzed, and hydrolyzed with aqueous base, asdescribed above, to yield the corresponding methyl2-(5-hydroxy-7-substituted-5',6',7',8'-tetrahydro-2'-naphthyl) aceticderivative. The latter is treated as described above to dehydrogenateand introduce the C-5 fiuoro, chloro, bromo, alkyl, alkoxy and alkylthiogroups.

The compounds of Formula X substituted at the 2-position are preparedfrom the corresponding 2-unsubstituted compounds of Formula X byesterifying the latter, and treating it with ethyl formate and sodiummetal to obtain the corresponding 2,2-hydroxymethylene derivative. Thelatter is treated with sodium hydride, then with chlorine gas, then withchromium trioxide in acetic acid and then heated to yield thecorresponding 2-chlor0 derivative. The 2-(2-chloro-2-naphthyl) aceticacid derivative is refluxed in sodium hydroxide, esterified withdiazomethane, oxidized with chromium trioxide in acetic acid and coupledby refluxing with difluoromethylene triphenyl phosphorane in benzene toobtain the corresponding 2,2-difluoromethylene derivatives of FormulaIX.

The Z-methyl substituents are added to the 2-unsubstituted compounds ofFormula X by esterifying the latter and treating it with sodium hydrideand alkyl halide, such as methyl iodide.' The Z-difluoromethylsubstituent is added by treating the 2-unsubstituted compounds ofFormula X successively with sodium hydride and diethyl carbonate, thenwith chlorodifluoromethane, then with aqueous 5% sodium hydroxide at 75C. followed by acidification with aqueous mineral acid and then finallyheating the resulting product to about 150 C. to yield the corresponding2-difluoromethyl derivatives of Formula X.

The 2,2-methylene substituents are introduced by treating the2-unsubstituted compounds of Formula X, with formaldehyde and an alkalimetal hydroxide. The 2,2- ethylene substituents are introduced byrefluxing the corresponding 2,2-methylene derivatives of Formula X withdiiodomethane in the presence of zinc-copper couple.

The various susbtituted tetralones are known and can be prepared byconventional methods. For example, the 5,7-disubstituted tetralones areprepared by treating a 1,3-disu'bstituted benzene derivatives with 2 ormore molar equivalents of succinic anhydride and two or more molarequivalents of aluminum chloride in nitro benzene or carbon disulfide toobtain the corresponding 4-oxo-4- (2,4'-disubstituted phenyl) butyricacids. The latter are reduced with a reducing agent such as sodiumborohydride or one molar equivalent of hydrogen in the presence ofplatinum to reduce the 4-oxo group to a 4-hydroxy group. The resultinghydroxy compounds are further hydrogenalized with a molar equivalent ofhydrogen in the presence of platinum catalyst to yield the corresponding4-(2',4'-disubstituted phenyl) butyric acids. These compounds arecyclized by refluxing with thionyl chloride and then treated with threeor more equivalents of aluminum chloride to yield the corresponding5,7-disubstituted-l-tetralones. When the benzene starting material issubstituted with two different groups, two tetralones are obtained. Forexample, if the starting material is l-chloro-3-methyl benzene,5-chloro-7-methyl-l-tetralone and 5-methyl-7-chloro-l-tetralone areobtained. The compounds are separated by conventional techniques, suchas distillation or chromatography, including gasliquid chromatography.

The 2-naphthyl acetic acids of formula X that exist as enantiomorphs canbe resolved by preparing the alkaloid base salts of the latter,resolving the resulting diasteroisomer salts by fractionalcrystallization and cleaving the resolved salts. The optical rotation ofa particular 2- naphthyl acetic acid is determined by polarirnetry.

The following examples are included to further illustrate the presentinvention and are not intended as limitations of the present invention.

Preparation 1 A mixture of 1925 g. of l-chloro 2 methoxynaphthalene, g.of acetyl chloride, 400 g. of aluminum chloride and 2.5 liters ofnitrobenzene are stirred for 60 hours at room temperature. The resultingmixture is then washed with dilute hydrochloric acid, dried over sodiumsulfate and evaporated to yield 2-acetyl-5-chloro- 6-methoxynaphthalene.The resulting acetyl product is added to a mixture of 39 g. of sulfurand g. of morpholine and heated to about C. for 3 hours. The mixture isthen added to 1 liter of concentrated hydrochloric acid and refluxed for3 hours. The mixture is then cooled, diluted with 6 liters of ice-waterand extracted with methylene chloride. The extracts are combined, washedwith water to neutrality, dried over sodium sulfate and evaporated toyield 2 (5 chloro 6 methoxy-2'-naphthy1) acetic acid.

In a similar manner,

2-(5',6-dimethyl-2'-naphthyl) acetic acid,2-(5'-bromo-6'-methoxy-2'-naphthyl) acetic acid,2-(5'-iodo-6'-methoxy-2-naphthyl) acetic acid,2-(5',6'-dimethoxy-2'-naphthyl) acetic acid,2-(5-methylthio-6'-chloro-2'-naphthyl) acetic acid, and2-(5-fluoro-6'-methoxy-2'-naphthyl) acetic acid,

are prepared from the corresponding 1,2-disubstituted naphthalenes bymeans of the above described process.

To a mixture of 50 g. of 2 (5 chloro 6' methoxy- 2-naphthy1) acetic acidand 250 ml. of diethyl ether, there are added 9 g. of diazomethane in250 ml. of diethyl ether. The mixture is stirred for 1 hour and thenflushed with nitrogen gas until colorless. The mixture is thenevaporated to yield methyl 2-(5'-chloro-6-methoxy-2- naphthyl) acetate.

To a mixture of 4.8 g. of sodium hydride in 100 ml. of1,2-dimethoxyethane, there are added 53 g. of the above methyl esterproduct. The mixture is stirred for 2 hours; then 19 g. of methylbromidein 200 ml. of 1,2-dimethoxyethane are slowly added. The resultingmixture is stirred for 3 hours at 25 C.; it is then diluted with l l. ofice-water and extracted -with diethyl ether. The extracts are combined,washed with water, dried over sodium sulfate and evaporated to yieldmethyl 2-(5-chloro- 6'-methoxy-2-naphthyl) propionate.

EXAMPLE 1 To a mixture of 0.4 g. of lithium aluminum hydride and 100 ml.of ethyl ether, a mixture of 2.3 g. of d and l 2-(6 methoxy 2' naphthyl)propionic acid and 100 ml. of ethyl ether. The mixture is stirred at 0C. for 30 minutes, then 10 ml. of ethyl acetate are added; one

hour later 18.5 ml. of water are added. The resulting mixture isfiltered and evaporated under reduced pressure. The resulting residue isadded to a mixture of 10 g. of chromium trioxide and 1 liter ofpyridine. The resulting reaction mixture is stirred under anhydrousconditions for 24 hours at 25 C., then 1 liter of ethyl acetate isadded. The resulting ethyl acetate mixture is filtered, washed with anaqueous saturated solution of sodium bisulfite and Water to neutrality,dried over sodium sulfate and evaporated under reduced pressure to yielda racemic mixture of 2 (6' methoxy 2 naphthyl)- propionaldehyde.

By employing a resolved 2-(2'-naphthyl) acetic acid derivative in theabove process, the corresponding 2-(2'- naphthyl) acid aldehydederivatives will be obtained. For example, if R2-(6'-methoxy-2'-naphthyl)propionaldehyde is prepared from R2-(6-methoxy2-naphthyl)propionic acid and S2-(6'-methoxy-2-naphthyl)propionaldehyde is prepared from S2-(6'-methoxy-2-naphthyl)propionic acid [these compounds have been namedin accordance with the Cahn-Ingold-Prelog system of naming opticalisomers; see R. S. Cahn, C. K. Ingold and V. Prelog, Experientia, vol.12, 81-95 (1956) and Carl R. Noller, Chemistry of Organic Compounds, pp.368-370, W. B. Saunders Co., Philadelphia (1965)].

Similarly,

2-( 1'-trifiuoromethyl-2-naphthyl propionaldehyde,

2-(5-methoxy-2'-naphthyl)-propionaldehyde,

2-(5'-methyl-2'-naphthyl)-acetaldehyde,

2-(5'-chloro-2'-naphthyl)-propionaldehyde,

2- 5 '-methylthio-2-naphthyl -2,2-methylacetaldehyde,

2- 6'-methylthio-2-naphthyl -2-difluoromethyl acetaldehyde,

2- (6'-methoxy-2'-naphthyl -2-difiuoromethyl acetaldehyde,

2-(6'-methyl-2-naphthyl)-propionaldehyde,

2- 6'-ethynyl-2'-naphthyl -p1'0pionaldehyde,

2-(6-acetyl-2'-naphthyl)-2,2-methylene acetaldehyde,

2-(6'-chloro-2-naphthyl)-propionaldehyde,

2- 7 '-methyl-2-naphthyl) -propionaldehyde,

2- 7'-methoxy-2-naphthyl -acetaldehyde,

2-(7'-chloro-2'-naphthyl)-propionaldehyde,

2-(7-methylthio-2-naphthyl)-2,2-methylene acetaldehyde,

2- 8'-ethylthio-2-naphthyl -butanal,

2- 5 '-chloro-6-methoxy-2'-naphthyl acetaldehyde,

2-( 5-ch1oro-6-methoxy-2-naphthyl) propionaldehyde,

2-(5'-bromo-6-methoxy-2-naphthyl) propionaldehyde,

2-(5,7-dichloro-2'-naphthyl)-acetaldehyde,

2-( 1-fiuoro-6'-methoxy-2-naphthyl) -propionaldehyde and 2- 5 ,7'-dimethyl-2-naphthyl) propionaldehyde are prepared from thecorresponding substituted 2- naphthyl acetic acids.

EXAMPLE 2 A mixture of 230 g. of 2-(5'-methoxy-2'-naphthyl) acetic acid,57 g. of lithium aluminum hydride and 10 liters of tetrahydrofuran isstirred for two hours at 0 C., then 1 liter of ethyl acetate is added.After one hour, 500 ml. of Water is added to the resulting mixture, themixture is stirred, filtered, dried over sodium sulfate and evaporatedunder vacuum. The residue is added to a mixture of 620 g. ofdicyclohexyl carbodiimide, 50 g. of anhydrous phosphoric acid and 2liters of dimethylsulfoxide. The resulting mixture is stirred for eighthours, then added to water, filtered to remove dicyclohexyl urea andextracted with ether. The combined ether extracts are filtered, washedwith water to neutrality, dried over sodium sulfate and evaporated toyield 2-(5'-methoxy-2- naphthyl acetaldehyde.

Similarly,

2-(1'-methoxy-2'-naphthyl) acetaldehyde,

16 2-(4-difiuoromethylthio-2-naphthyl) propionaldehyde,2-(5'-fluoro-2'-naphthyl) acetaldehyde, 2-(5-methylthio-2'-naphthyl)propionaldehyde, 2-(5'-chloro-2'-naphthyl) acetaldehyde,2-(5'-trifiuoromethyl-2'-naphthyl)-2,2-difluoromethylene acetaldehyde,2-(6'-fiuoro-2'-naphthyl) propionaldehyde, 2-(6'-rnethyl-2-naphthyl)acetaldehyde, 2-(6'-methoxy-2'-naphthyl) acetaldehyde,2-(6-difluoromethoxy-2'-naphthyl)-2-difiuoromethyl acetaldehyde,2-(6-difluoromethoxy-2'-naphthyl) acetaldehyde,2-(6-methoxy-2'-naphthyl) butanal, 2- 7-fiuoro-2'-naphthyl-2-propionaldehyde, 2-(7-vinyl-2'-naphthyl)-2-propionaldehyde,2-(7'-methylthio-2-naphthyl)-2-butanal, 2-(7'-rnethylthio-2'-naphthyl)acetaldehyde, 2-(7'-chloro-2'-naphthyl)-2,2-methylene acetaldehyde, 2-8-trifiuoromethyl-2'-naphthyl -2,2-methylene acetaldehyde, 2- 5,7'-dimethoxy-2-naphthyl) propionaldehyde, 2-(5,6'-dimethyl-2-naphthyl)propionaldehyde, and

2-(5'-bromo-6'-methoxy-2'-naphthyl) propionaldehyde are prepared,respectively, from the corresponding compounds by means of the aboveprocess:

2-(l-methoxy-2'-naphthyl) acetic acid,

2-(4'-difluoromethylthio-2'-naphthyl) propionic acid,

2-(5'-methylthio-2-naphthyl) propionic acid,

2-(5-chloro-2-naphthyl) acetic acid,

2-(5'-trifluorornethyl-2'-naphthyl)-2,2-difluoromethylene acetic acid,

2-(6'-fiuoro-2'-naphthyl) propionic acid,

2-(6"rnethyl-2'-naphthyl) acetic acid,

2-(6-methoxy-2-naphthyl) acetic acid,

2- 6'-difluor0methoxy-2-naphthyl -2-difiuoromethyl acetic acid,

2-(6-difluoromethoxy-2'-naphthyl) acetic acid,

2-(6'-methoxy-2-naphthyl) butyric acid,

2-(7fluoro-2'-naphthyl) propionic acid,

2-(7'-vinyl-2'-naphthyl) propionic acid,

2-(7-methylthio-2-naphthyl) butyric acid,

2( 7-methylthio-2'-naphthyl) acetic acid,

2-(7-chloro-2'-naphthyl)-2,2-methylene acetic acid,

2- 8'-trifiuoromethyl-2-naphthyl -2,2-methylene acetic acid,

2-(5',7-dimethoxy-2-naphthyl) propionic acid,

2-(5,6-dimethyl-2'-naphthyl) propionic acid, and

2-(5-bromo-6'-methoxy-2-naphthyl) propionic acid, re-

spectively, by means of the above process.

EXAMPLE 3 A mixture of 46 g. of 2-(7'-methoxy-2'-naphthyl) propionicacid, in 200 ml. of tetrahydrofuran is treated with 6 g. of diborane in500 ml. of tetrahydrofuran and stirred for one hour at room temperature(about 23 C.). The mixture is allowed to stand for one hour after beingdiluted with 50 ml. of aqueous acetone, then 1 liter of diethyl etherare added. The resulting mixture is Washed with water, dried over sodiumsulfate and evaporated. The resulting residue is added to a mixture isstirred under anhydrous conditions for 24 hours at 25 C.; then 1 literof ethyl acetate is added. The mixture is then filtered, washed with anaqueous acidified solution of sodium bisulfite and water to neutrality,dried over sodium sulfate and evaporated under reduced pressure to yield2-(7'-methoxy-2-naphthyl) propionaldehyde.

Similarly,

2-(5'-methy1-2'-naphthyl) propionaldehyde,2-(5-difluoromethoxy-2-naphthyl) propionaldehyde,2-(5-difiuoromethoxy-2-naphthyl) acetaldehyde,2-(5-methylthio-2'-naphthyl) acetaldehyde,

2- 6'-ethyl-2'-naphthy1 pro pionaldehyde, 2-(6-chloro-2'-naphthyl)-2-difiuoromethyl acetaldehyde,

ene glycol (distilled over sodium hydroxide) and 0.8 g. ofp-toluenesulfonic acid monohydrate is refluxed for 12 hours with a watertrap. Aqueous sodium bicarbonate solution is then added to the cooledmixture and the organic phase is separated, Washed with water, driedover anhydrous sodium sulfate and evaporated to dryness to yieldethylenedioxy 2-(5'-methoxy-2'-naphthyl) ethane which is recrystallizedfrom acetone:hexane.

Similarly, by employing glycerine,

2,3-dihydroxybutane, 2,2-dimethyl-1,3-dihydroxypropane,2,2-diethyl-1,3-dihydroxypropane, 2,2-diphenyl-1,3-dihydroxypropane,2,2-dicyclopentyl-1,3-dihydroxypropane,2-cyclohexylmethyl-1,3-dihydroxypropane,2-ethyl'2-(2'-cyclopropylethyl)-l,3-dihydroxypropane,1,3-dihydroxypropane,

3 ,4-dihydroxyhexane, 2,3-dihydroxynonane and 2,4-dihydroxypentane inplace of ethylene glycol in the above process, the correspondingglycerol,

butane-2,3-dioxy,

2,2-dimethylpropane-1,3-dioxy,

2,2-diethylpropane-1,3-dioxy,

2,2-diphenylpropane-1,3-dioxy,

2,2-dicyclopentylpropane-1,3-dioxy,

2-cyclohexylmethylpropane-1,3-dioxy,

2-ethyl-2-(2'-cyclopropylethyl)propane-1,3-dioxy,

propane-1,3-dioxy,

hexane-3,4-dioxy,

nonane-2,3-dioxy, and

pentane-2,4-dioxy cyclic acetals of 2-(5'-methoxy- 2-naphthyl)acetaldehyde,

respectively, are obtained.

By employing the 2-(2'-naphthyl) acetaldehyde derivatives prepared inExamples 1, 2, 3 and 4 in the above process, the correspondingethylenedioxy cyclic acetals thereof are obtained.

EXAMPLE 6 A mixture of 21 g. of 2-(6-methoxy-2-naphthyl)propionaldehyde, 500 ml. of ethanol and 20 drops of perchloric acid areallowed to stand for eight hours at room temperature under anhydrousconditions. The mixture is then diluted with 500 ml. of aqueous 1%sodium bicarbonate; and extracted with methylene chloride. The combinedextracts are washed with water to neutrality, dried over magnesiumsulfate and evaporated to yield are similarly prepared by employingmethanol, propanol, isopropano], pentanol, cyclopropanol, cyclopentanol,cyclohexauol, benzyl alcohol and phenethanol respectively, in place ofethanol in the above process.

20 By using the 2-(2'-naphthyl) acetaldehyde derivatives prepared inExamples 1, 2, 3 and 4 in the above process, the corresponding diethoxyacetals thereof are obtained.

EXAMPLE 7 Water is added to a solution of 20.1 g. of2-(6-methoxy-2'-naphthyl) acetaldehyde and 500 ml. of ethanol until thesolution is faintly turbid; the turbidity is removed by the addition ofseveral drops of ethanol. To this resulting solution then is added 25 g.of semicarbazide hydrogenchloride and 50 g. of sodium acetate. Theresulting mixture is refluxed for 10 minutes and then is allowed to coolat 0 C. for 24 hours. The cooled mixture is then filtered and theresulting crystals are washed with several portions of ice cold ethanolto yield the semicarbazone of 2-(6'methoxy-2'-naphthyl) acetaldehyde.The semicarbazone is recrystallized from water: ethanol (311).

In a similar manner, the semicarbazones of the 2-(2- naphthyl)acetaldehyde derivatives of Examples 1, 2, 3 and 4 are prepared by meansof the above process. For example, the semicarbazone of2-(5'-methoxy-2'-naphthyl) acetaldehyde is prepared by employing2-(5'-methoxy-2'-naphthyl) acetaldehyde in the above process.

EXAMPLE 8 A mixture of 50 g. of 2-(5'-methoxy-2-naphthyl) acetaldehyde,50 g. of hydroxylamine hydrogenchloride, 500 ml. of pyridine and 500 ml.of absolute ethanol are refiuxed for 8 hours. The resulting mixture iscooled and evaporated under reduced pressure. The resulting residue istriturated with 250 ml. of cool water; the resulting aqueous mixture isthen filtered. The resulting crystals are washed thoroughly with severalportions of water to yield 2-(5'methoxy-2'-naphthyl) acetaldoxime.

Similarly, by employing the 2-(2-naphthyl) acetaldehyde derivativesprepared in Examples 1, 2, 3 and 4 in the above process, thecorresponding oxime derivatives thereof can be' obtained. For example,2-(5'-methyl-2- naphthyl) acetaldoxime is prepared by using 2-(5-methyl-2'-naphthyl) acetaldehyde in the above process.

1-methoxyimino-2-( 6-methoxy-2'-naphthyl) ethane, 1-ethoxy-imino-Z-(6'-methoxy-2'-naphthyl) ethane,l-i-propoxyimino-2-(6'-methoxy-2'-naphthyl) ethane andl-benzyloxyimino-2-(6'-metl1oxy-2-naphthyl) ethane, are prepared byemploying methoxyamine, ethoxyamine, i-propoxyamine and benzyloxyamine;respectively, in place of hydroxylamine in the above described process.

EXAMPLE 9' A mixture of 201 g. of 2-(7'-methyl-2'-naphthyl)acetaldehyde, 200 g. of acetic anhydride, 68 g. of borontrifiuoride arestirred for 8 hours at about 5 C. The resulting reaction mixture isevaporated under reduced pressure to yield 2-(7'-methyl-2'-naphthyl)ethylidenediacetate.

In a similar manner, the acylals of the 2-(2'-naphthy1) acetaldehydederivatives prepared in Examples 1, 2, 3 and 4 are prepared by means ofthe above described process. For example, 2-(5'-methylthio-2'-naphthyl)ethylidenediacetate is prepared from 2-(5-methylthio-2-naphthyl)acetaldehyde by means of the above process.

2-(5'-methoxy-2-naphthyl) ethylidenedipropionate, 2- (5-methoxy 2'naphthyl ethylidenedicaproate, 2 (5'- o methoxy-2-naphthyl)ethylidenedivalerate, and 2-(5'-methoxy 2' naphthyl) ethylidenesuccinateare prepared by utilizing propionic anhydride, caproic anhydride,valeric anhydride and succinic anhydride, respectively, in place ofacetic anhydride in the above described process.

EXAMPLE 10 To a refluxing mixture of 18.5 g. of 2-(7'-methylthio-2'-naphthyl) propionaldehyde, 18.5 g. of hydrazine and 350 ml. ofethanol, there is added 5 drops of glacial acetic acid. The mixture isrefluxed for an additional 5 minutes 21 and sufficient ethanol is addedto obtain a clear refluxing solution. The solution is cooled andfiltered. The resulting crystals are thoroughly washed with cold C.)ethanol. The crystals are recrystallized from ethanol to yield thehydrazone or 2-(7'-methylthio-2-naphthyl) propionaldehyde.

Similarly, the hydrazones of the 2-(2'-naphthyl) acetaldehydederivatives of Examples 1, 2, 3 and 4 are prepared by means of the abovedescribed process. For example, the hydrazone of2-(4'-chloro-2-naphthyl)-2,2- methyleneacetaldehyde is prepared from2-(4-chloro-2'- naphthyl)-2,2-methylene acetaldehyde by means of theabove described process.

EXAMPLE 11 Part A.A mixture of 21.5 g. of 2-(6'-methoxy-2- naphthyl)propionaldehyde and 500 ml. of methylene chloride are cooled to 0 C. andsaturated with anhydrous ammonia. The mixture is stirred for 12 hourswhile maintaining the temperature at 0 C. and continuing to bubble inammonia. The resulting reaction mixture is then evaporated to yield1-amino-2-(6-methoxy-2'naphthyl) propanol.

Part B.The above product is warmed to 50 C. under vacumm for 8 hours toyield 1-imino-2-(6'-methoxy-2'- naphthyl) propane.

In a similar manner, the amino alcohols and aldimines of the'2-(2-naphthyl) acetaldehyde derivatives of Examples 1, 2, 3 and 4 areprepared by means of the above described process. For example,1-imino-2-(1'-ethyl-2- naphthyl)-2,Z-difiuoromethyleneethane is preparedfrom 1-amino-2-(1'-ethyl-2naphthyl)-2,2 difluoromethylene ethanol bymeans of the process described in Part B above, and1-amino-2-(1-ethyl-2'-naphthy1)-2,2-difluoromethyleneethanol is preparedfrom 2-(l'-ethyl-2'-naphthyl)-2,2-difluoromethylene acetaldehyde bymeans of the above process described in Part A described above.

I-methylamino-Z-(6-methoxy-2' naphthyl) propano l,1-ethylamino-2-(6'-methoxy-2 naphthyl) propanol, 1-1-propylamino-2-(6-methoxy 2 naphthyl) propanol, 1-benzylamino-Z-(6'-methoxy-2-naphthyl) propanol and 1-phenylamino-Z-(6'-rnethoxy 2' naphthyl) propanol are prepared byemploying methylamine, ethylam1ne, 1sopropylamine, benzylamine, andphenylamine, respectively, 1n place of ammonia in the process describedabove 1n Part A. By employing the thus prepared alkyl-, aralkylandarylamino-Z-(6'-methoxy-2-naphthyl) propanol s 1n the process describedabove in Part B, 1-methyl1m1no-2-(6- methoxy-2-naphthyl) propane,l-ethylimino 2 (6-methoxy-2'-naphthyl) propane, l-i-propylimino 2(6'-methoxy-2-naphthyl) propane 1 benzylimrno- 2 (6-methoxy-2-naphthyl)propane and l-phenylrmino 2 (6 methoxy-2'-naphthyl) propane,respectively, are obtained.

EXAMPLE 12 To 600 ml. of a 40% solution of sodium bisulfite, is added150 ml. of ethanol and 100 g. of 2-(6'-methoxy-2'- naphthyl)propionaldehyde in 500 ml. of ether The resulting mixture is stirred for3 hours; then it IS filtered to yield the sodium bisulfite additionproduct of 2-(6 methoxy-2'-naphthyl) propionaldehyde.

Similarly, the 2-(2-naphthyl) acetaldehyde derivatives prepared inExamples 1, 2, 3 and 4 are employed in the above process to prepare thecorresponding sod1um b1- sulfite addition products thereof. For example,the sodrum bisulfite addition product of 2-(5'-methoxy-2'-naphthyl)acetaldehyde is obtained by using 2-(5'-methoxy-2-naphthyl) acetaldehydein the above process.

EXAMPLE 13 To a mixture of 50 g. of borontribromide in 250 ml. ofmethylene chloride, cooled to --80 C., there is added 21.4 g. of 2(6'-methoxy-2'-naphthyl) propionaldehyde.

22 The mixture is allowed to warm to room temperature over one hour. Thereaction mixture is then diluted with 250 ml. of water and filtered; theorganic layer is then separated oflf. The organic layer is washed withwater to neutrality, dried over sodium sulfate and evaporated to yield2-('6'-hydroXy-2'-naphthyl) propionaldehyde.

By employing 2-(6-methylthio-2'-naphthyl) acetaldehyde in the aboveprocess, 2-(6-thio-2-naphthyl) acetaldehyde is obtained.

Similarly, the methoxy, methoxymethyloxy, difluoromethoxy, methylthio,methoxymethylthio or difluoromethylthio substituted 2-(2-naphthyl)acetaldehyde derivatives of Examples 1, 2, 3 and 4 are employed in theabove process, give the corresponding hydroxy or thio substituted2-(2'-naphthyl) acetaldehyde derivatives. For example, 2(5-thio-2'-naphthyl)-2,2-methyleneacetaldehyde is prepared from2-(5'-isopropylthio-2'-naphthyl)- 2,2-methyleneacetaldehyde by means ofthe above process.

EXAMPLE 14 No. of rats 33 Dose range tested mg./rat 0.1-09

Relative potency to phenylbutazone (phenylbutazone=1) EXAMPLE 15 Theanalgesic activity of the bisulfite addition product of2-(6'-methoxy-2'-naphthyl) propionaldehyde was compared with that ofaspirin and phenylbutazone. The test used was based on the test ofRandall & Selitto, Arch. Int. Pharmacodyn 111, 409419 (1957) andconsisted of administering orally by gavage 30 or mg. per kilogram ofbody weight, the analgesic compound with water (20 ml. per kilogram ofbody weight) in eight male rats weighing between to 200 grams. A controlgroup received an equivalent volume of water. One hour after theadministration of the compound, 0.10 ml. of a 20% yeast suspension (RedStar Brand, primary dry type 600 in 0.9% saline) was injected into thesub-plantar area of the left hind paw of each rat in the drug treatedgroup and the control group. The purpose of the injection is to provokethe formation of inflammatory edema.

Two hours after the injection of yeast, the control paw and the yeastinflammed paw of each rat in the drug treated group and in the controlgroup successively were compressed at the plantar surface by a stud witha surface area of about 9 mm? attached to a force displacementtransducer (model FT03 Grass) which was driven at a constant rate. Theinduced pressure was recorded on a strip chart recorder. When a painreaction was evoked from the rat by the application of pressure, theamount of pressure was recorded; the pressure was recorded in paperpressure units (0-100). The ditference between the amount of pressurerequired to evoke pain reaction between the control paw and inflammedpaw among the drug treated group of rats and control group of ratsserves as an index of analgesic activity. The measure of analgesicactivity in the rats is expressed in percent, in reference to that ofthe inflamed paw and non-inflammed paw. [(Pressure units to evoke painin inflammed paw/pressure units to evoke pain in control paw) X 100].The results are summarized in the following table.

Degree of analgesic in percent with reference to the controls additionof 2- (6-metl1oxy-2'- Dose administered naphthyl) Phenylin mg/kg.acetaldehyde Aspirin butazonc EXAMPLE 16 The analgesic activity ofseveral 2-(2-naphthyl) acetaldehyde derivatives was compared with thatof aspirin and phenylbutazone. The test was based on the test of Randall& Sellitto, Arch. Int. Pharmacodyn 111, 409-419 (1957) and consisted ofadministering orally by gavage 30, 90 or 100 mg. per kilogram of bodyweight, the analgesic compound with water (20 ml. per kilogram of bodyweight) in eight male rats weighing between 120 to 200 grams. A controlgroup received an equivalent volume of water. One hour after theadministration of the compound, 0.10 ml. of a 20% yeast suspension (RedStar Brand, primary dry type 600 in 0.9% saline) was injected into thesub-planar area of the left hind paw of each rat in the drug treatedgroup and the control group. The purpose of the injection is to provokethe formation of inflammatory edema.

At hour one after the injection of yeast, the control paw and the yeastinflammed paw of each rat in the drug treated group in the control groupsuccessively were compressed at the plantar surface by a stud with asurface area of about 9 mm. attached to a force displacement transducer(model FTO3 Grass) which was driven at a constant rate. The inducedpressure was recorded on a strip chart recorder. When a pain reactionwas evoked from the rat by the application of pressure, the amount ofpressure was recorded; the pressure was recorded in paper pressure units(-100). The difference between the amount of pressure required to evokepain reaction between the control paw and inflammed paw among the drugtreated group of rats and control group of rats serves as an index ofanalgesic activity. The measure of analgesic activity in the rats isexpressed in percent, in reference to that of the inflammed paw andnon-inflammed paw. [(Pressure units to evoke pain in inflammedpaw/pressure units to evoke pain in control paw) X 100]. The results aresummarized in the following table.

The anti-pyretic activity of 2-(6'-methoxy-2-naphthyl) propionaldehydewas compared to the anti-pyretic activity of aspirin.

Anti-pyretic activity.Female rats weighing 90-100 grams were used. Thenormal rectal temperature of the rats was recorded at hour 0, followedby the injection of 2 ml. of yeast suspension (the yeast suspension isprepared by suspending one cake of Fleischmans yeast in 22 ml. 0.9%NaCl) subcutaneously (1 ml. dorsally, 1 ml. ventrally). The injectionsited are massaged to spread the suspension beneath the skin. The yeastinjection induces elevated body temperature. At hour 17, the rats weremassaged again to stimulate a further increase in body temperature. (Itwas found that handling the rats at the time the second temperature wastaken resulted in a rise in body temperature.) At hour 18, the secondrectal temperature was recorded, after which the test material wasadministered orally by gavage in 1 ml. aqueous vehicle. (The aqueousvehicle consists of 0.9% NaCl, 0.4% polysorbate 80, 0.5% carboxymethylcellulose, 0.9% benzyl alcohol and water.) The third rectal temperaturewas obtained two hours after administration of the test material.

The degree of anti-pyretic activity was measured as a reduction intemperature (F.) from the second to the third temperature readings(temperature at hour 18- temperature at hour 20) with respect to acontrol. The results are shown in the following table.

No. Doses Relative of tested, potency to Compound rats mgJrat aspirin 12(6-methoxy-2-naphthyl) proplon- 10 0.2 and 0.6. 15

aldehyde.

1 Aspirin=1.

The above ingredients are thoroughly mixed and processed into singlescored tablets, one tablet being administered every three to four hours.

EXAMPLE 19 Ingredients: Quantity per tablet, mgs.2-(6-methoxy-2-naphthyl) propionaldehyde 60 Cornstarch 38 LactoseMagnesium stearate 2 The above ingredients are mixed intimately andpressed into single scored tablets.

EXAMPLE 20 Ingredients: Quantity per capsule, mgs.2-(5'-methoxy-2'-naphthyl) propionaldehyde 15 Lactose 225 Dectrose 10The above ingredients are mixed and introduced into a No. 1 hard-shellgelatin capsule.

EXAMPLE 21 Ingredients: Qpantity per capsule, mgs. 1,1dimethoxy-2-(5'-methoxy 2' naphthyl) ethane 25 Lactose 225 CHRIRZ cna aa a J 11.

25 wherein R and R are alkoxy having from 1 to 6 carbons,

cycloalkoxy having from 3 to 7 carbons, cycloalkylmethoxy having from 4to 8 carbons, 2-cycloalkylethoxy having from 5 to 9 carbons,S-cycloalkylpropoxy having from 6 to 10 carbons, monocyclic arylmethoxyhaving from 7 to 13 carbons, Z-phenylethoxy, 3-phenylpropoxy,alkanoyloxy having from 1 to 12 carbons, cycloalkanoyloxy having from 4to 8 carbons, cycloalkylacetoxy having from 5 to 9 carbons,cycloalkylpropionyloxy having from 6 to 10 carbons, or monocyclicarylacetoxy having from 8 to 14 carbons; or R and R taken together are0x0;

one of R and R is hydrogen and the other is hydrogen, methyl, ethyl ordifluoromethyl; or R and R taken together are methylene, ethylene orhalomethylene;

R and R each are alkyl having up to 6 carbons, cycloalkyl having from 3to 7 carbons, alkoxymethyl having up to 7 carbons, trifluorornethyl,vinyl, ethynyl, fluoro, chloro, alkoxy having up to 6 carbons,difluoromethoxy, alkoxymethyloxy having up to 7 carbons, alkylthiohaving up to 6 carbons, difluoromethylthio, alkoxymethylthio having upto 6 carbons, alkylthiomethylthio having up to 7 carbons, phenyl oralkylsubstituted phenyl having up to 12 carbons; and

R is fiuoro, chloro or bromo.

2. The method according to claim 1 wherein R and R are methoxy, ethoxy,propoxy, cyclopentyloxy, cyclohexyloxy, benzyloxy, phenethyloxy,tolyloxy, acetoxy, propionyloxy, valeryloxy, caproyloxy,cyclopentylcarbonyloxy, cyclohexylcarbonyloxy, phenylacetoxy ortolylacetoxy; or R and R taken together are oxo;

one of R and R is hydrogen, the other is hydrogen,

26 methyl or difluoromethyl; or R and R taken together are methylene ordifiuoromethylene;

R and R each are methyl, ethyl, isopropyl, cyclopropyl, trifiuoromethyl,vinyl, ethynyl, fiuoro, chloro, methoxy, methoxymethyloxy,difiuoromethoxy, methylthio, methoxymethylthio, difiuoromethylthio orphenyl.

3. The method according to claim 2 wherein the cornpound is selectedfrom the group represented by Formula A.

4. The method according to claim 3 wherein one of 'R and R is hydrogenand the other is methyl.

5. The method according to claim 4 wherein R and R are methoxy orethoxy, or R and R taken together are 6. The method accordinng to claim5 wherein R is methyl.

7. The method according to claim 5 wherein R is methylthio.

8. The method according to claim 5 wherein R is methoxy.

9. The method according to claim 8 wherein the compound is2-(6-methoxy-2'-naphthyl)propionaldehyde.

References Cited UNITED STATES PATENTS 2,542,937 2/1951 Miescher et a1.260-699 STANLEY J. FRIEDMAN, Primary Examiner US. (:1. X.R. v 260-599,600, 609 R, 611A; 424-305, 340

